Prostate cancer is one of the most common cancers in men, comprising approximately 33% of all cancers. In 1996, 317,000 new patients will be diagnosed with prostate cancer. Fifty percent of these (158,550) will undergo radical prostatectomy. Statistics indicate that 1.5 billion dollars are spent as direct medical expenses and an additional 2.5 billion dollars as indirect costs in the management of prostate cancer. It is also anticipated to further increase due to the steep rise in population of patients older than 65 years. Current estimates are that 85,800 radical prostatectomies are performed annually.
At present, radical prostatectomy is clearly the most effective treatment for prostate cancer resulting in a disease-free survival (DFS) at 10 years in up to 85% of patients. However, cure is only possible if the cancer is organ confined. Several long-term studies of radical prostatectomy show that biochemical failure at 10 years is seen in as many as 58% of patients with positive margins, 57% with seminal vesicle-positivedisease, and 100% with lymph nodal disease. It is therefore essential to accurately stage prostate cancer and avoid radical interventions to potentially incurable patients. Inaccurate staging adds significantly to the cost of managing prostate cancer. It is therefore imperative to construct accurate and cost-effective staging tools. Currently, however, understaging of prostate cancer occurs in 40-60% of clinically localized prostate cancer. Margin-positive disease remains the biggest problem confronting clinicians attempting surgical management of prostate cancer. In recent studies, the incidence of margin positive disease after radical prostatectomy is very high (37-63%; mean 45%). The mean incidence of margin positivity and seminal vesicle involvement is 17-47%, while nodal involvement is 2-10.5%. Although an overwhelming number of staging studies are currently available to the clinician, including digital rectal examination (DRE), prostate specific antigen (PSA), prostate specific antigen density (PSAD), PSAD corrected for transition zone of prostate (PSAT), sextant prostate biopsy, transrectal ultrasound guided (TRUS) capsular and seminal vesicle biopsies, molecular staging (PCR-PSA), endorectal MRI, pelvic CT, CT-guided lymph node biopsies, antigen directed monoclonal antibodies (Onco Seint; "CYTOGEN"), bone scintigraphy and staging lymph node dissection, none are very accurate. This lack of sensitivity and specificity results in many patients undergoing multiple staging procedures. These multiple staging procedures and resultant unindicated surgical interventions currently add significantly to the cost of managing prostate cancer.
Because of the dire need for strategies to reduce staging costs, several investigators have studied this issue. One of the earliest studies was by Oesterling and associates, who reported on the role of serum PSA in reducing the need for bone scintigraphy (Oesterling, J. E. [1995] Urology 46:26-33; Oesterling, J. E. [1993] Urol. Clin. North Am. 20:705-711). A number of other studies indicating the lack of need of certain single modalities of staging such as bone scintigraphy and node dissection prompted several investigators to study a combination of variables to construct relatively uncomplicated nomograms for clinicians managing prostate cancer. Several nomograms have been proposed to predict probabilities of extracapsular and metastatic disease. These nomograms however are variable and not highly accurate. Examples of such nomograms include those by Partin, Badalament, and Narayan (Partin, A. W., J. Yoo, H. B. Carter et al. [1993] J. Urol. 150:110-114; Partin, A. W., P. C. Walsh [1994] J. Urol. 152:172-173;Narayan, P., V. Gajendran, S. P. Taylor et al. [1995] Urology 46:205-21; R., M. Miller, P. Peller et al. [1996] J. Urol. 156:1375-1380). While Partin and associates utilize the large database of accurately studied prostate cancer patients at Johns Hopkins Institute, its major drawback is the use of DRE to differentiate T2a/b and T2c patients. A second problem may be the small-sized cancers and select population seen at Johns Hopkins Institute. Recently, Badalament and associates have constructed a backwards stepwise logistic regression algorithm based on nuclear imaging, DNA ploidy, nuclear grade, serum PSA, percent of tumor involvement, number of positive sextant cores, preoperative Gleason score, and more than 5% of base and/or apex involvement in 210 patients (Badalament et al., supra). They report an 86% sensitivity, 71% specificity, 73% positive predictive value, and 85% negative predictive value. Their input data required several specialized investigations such that its day to day utility and cost-effectiveness remain to be established. Some of the input variables they used such as DNA ploidy are also very controversial in that several investigators have questioned their utility. They also have a relatively small number of patients (N=200), so the utility needs testing in large numbers. In the other study (N=813), pooled patient data from two major universities was combined with data from a major HMO as well as data from the private practice of prominent urologists. (R) This series, however, used TRUS-guided systemic biopsy data rather than DRE to clinically stage patients.
Neural networks utilize the concept of artificial intelligence (Niederberger, C. S., L. I. Lipshultz, D. J. Lamb [1993] Fertil. Steril. 60:324-330; Niederberger, C. S. [1995] J. Urol. 153; Wasserman, P. [1993] Neural Computing: Theory and Practice, Van Nostrand Reinhold, New York, pp. 1.1-11; Wasserman, P. [1993] Advanced Methods in Neural Computing, Van Nostrand Reinhold, New York, pp. 1-60; Fu, L. [1994] Neural Networks in Computer Intelligence, McGraw-Hill, Inc., New York, pp. 155-166). Attempts have been made to apply this technology to certain medical problems, including the prediction of myocardial infarction in patients using family history, body weight, lipid profile, smoking status, blood pressure, etc. (Lamb, D. J., C. S. Niederberger [1993] World J. Urol 11: 129-136; Patterson, P. E., [1996] Biomed Sci. Instrum. 32:275-277; Pesonen, E. M. Eskelinen, M. Juhola [1996] Int. J. Biomed Comput. 40:227-233; Ravery, V., L. A. Boccon Gibod, A. Meulemans et al. [1994] Eur. Urol. 26:197-201; Snow, P. B., D. S. Smith, W. J. Catalona [1994] J. Urol. 1923-1926;Stotzka, R., R. Manner, P. H. Bartels, D. Thompson [1995] Anal. Quant. Cytol Histol. 17:204-218; Yoshida, K., T. Izuno, E. Takahashi et al. [1995] Medinfo 1:838-842; Webber, W. R., R. P. Lesser, R. T. Richardson et al. [1996] Electoencephalogr. Clin. Neurophysiol. 98:250-272). Snow and associates also attempted to use a neural network in the detection of prostate cancer and prediction of biochemical failure following radical prostatectomy (Snow et al., supra).
Several investigators have attempted to construct probability tables and nomograms by combining the results of the above-mentioned tests (Partin et al., supra; Partin and Walsh, supra; Narayan et al., supra). As previously discussed, these nomograms only provide a probability percentage, but currently there are no recommendations about cut points for these percentages which can help patients and physicians in decision making. Our testing of these nomograms using a 15 to 20% acceptable risk for margin positive disease revealed a positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, and accuracy of 38%, 70%, 72%, 36%, and 48%, respectively for predicting margin positivity in prostate cancer. A cutoff point of 5% probability for the nomogram predicting S.V. positivity resulted in a PPV, NPV, sensitivity, specificity, and accuracy of 9%, 97%, 73%, 55%, and 56%, respectively. A cut off point of 5% probability for the nomogram predicting L.N. positivity resulted in statistical measures of 9%, 75%, 66%, and 67%, respectively.
The currently available staging modalities for prostate cancer are rather inadequate for accurate staging. Only 60% of cancers clinically diagnosed to be locally confined turn out to be so on final pathology. Accurate preoperative staging is important; patients with positive margins with or without seminal vesicle involvement and lymph nodal spread have a distinctly poorer prognosis than those with organ confined disease. Radical prostatectomy in patients with organ confined disease on final pathological analysis results in survival comparable to that of age-matched controls without prostate cancer. Therefore, it is easier to make a distinction between patients with organ confined versus margin positive and regional disease for management decisions.